Camptothecin, (herein referred as CPT) a natural alkaloid isolated from the bark of Camptotheca acuminata is known to possess antitumor activity by inhibition of nucleic acid synthesis. Due to some severe side effects of this natural compound, various camptothecin derivatives have been synthesized with reduced toxicity and enhanced antitumor activity. One such compound is 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin hydrochloride trihydrate (Generic name: irinotecan; herein referred to as CPT-11).
Camptothecin analogs such as CPT-11 and others are derived by a chemical synthesis from CPT, which is obtained from plant sources. However, the amount of CPT obtained from natural plant source is extremely low and the purity of the final CPT-11 is also low (˜97%) due to the contamination of related natural products. Further, the demand for CPT-11 is increasing and the supply of CPT is gradually reducing. Several reports have appeared on the total synthesis of CPT and CPT-11, but till recently no synthetic method has been exploited for commercial production.
Various methods for the synthesis of camptothecin and camptothecin analogs are known in the art. These synthetic methods include (i) methods in which naturally occurring camptothecin is synthetically modified to produce a number of analogs and (ii) totally synthetic methods.
U.S. Pat. Nos. 4,604,463; 4,545,880; and 4,473,692 and European patent application No. 0074256 are examples of the former type of synthetic strategy. All these methods require naturally occurring camptothecin, which is difficult to isolate and hence these methods are not suitable for large scale production of camptothecin or analogs.
Examples of total synthetic routes to camptothecin and camptothecin analogs can be found in the following references: J. Org. Chem., 40 (14), 2140-1 (1975); J. Chem. Soc., Perkin Trans 1, (5), 1563-8 (1981); J. Amer. Chem. Soc., 94 (10), 3631-2 (1972); J. Chem. Soc. D, (7), 404 (1970), U.S. Pat. No. 4,031,098, Chem. Pharm. Bull., 39, 1446-54 (1991); J. Org. Chem., 62, 6588-97, (1997).
The best method known till now is to synthesize the two key intermediates (1 and 4) or (3 and 4) and condense by Friedlander reaction to give either CPT or 7-ethyl-10-hydroxycamptothecin (herein referred to as SN-38) via its methyl ether and then converting SN-38 to CPT-11 (Scheme-1)

Patent Application no. US2004/0106830 A1 discloses the preparation of AB ring (2-amino-5-hydroxycamptothecin) for CPT-11 synthesis starting from either 5-hydroxy-2-nitrobenzaldehyde or from 5-benzyloxy-2-nitrobenzaldehyde as shown in the scheme 2

There are several disadvantages in making 2-amino-5-hydroxyprpiophenone from 5-hydroxy-2-nitrobenzaldehyde, which itself is more expensive and involves several steps for its synthesis. In the first step, the Grignard reaction results in substantial formation of byproducts and the isolation of pure compound (9) is tedious. Further, in the final reduction of compound 10, it is difficult to avoid small amounts of 2-amino-5-hydroxypropylbenzene as byproduct, due to the reduction of the carbonyl group.